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New class of cancer drugs

A team of Vanderbilt University Medical Center investigators has developed a group of chemical compounds that could represent a new class of drugs for treating cancer.

The compounds are the first selective inhibitors of the protein phospholipase D (PLD), an enzyme that has been implicated in multiple human cancers including breast, renal, gastric and colorectal.

The new inhibitors, reported in the February issue of Nature Chemical Biology, block the invasive migration of breast cancer cells, supporting their further development as antimetastatic agents. They will also be useful tools for understanding the complex roles of PLD in cellular physiology.

The team – led by H. Alex Brown, Ph.D., professor of Pharmacology and Craig Lindsley, Ph.D., associate professor of Pharmacology and Chemistry – developed and screened compounds for activity against PLD1 and PLD2, two isoforms of the enzyme. They demonstrated that the compounds act directly on the PLD enzymes (using purified proteins).

Using a cell migration assay developed in the lab of Carlos Arteaga, M.D., director
of the Vanderbilt-Ingram Breast Cancer SPORE (Specialized Program of Research Excellence), they were able to show that the inhibitors blocked the invasive migration behavior of three different breast cancer cell lines.

“These inhibitors are the key tools we need to really probe the biology, and we’re obviously hoping to develop them for therapeutic applications too,” Brown said.

The researchers will now optimize their new compounds for in vivo studies and to give them characteristics compatible with being good medications. In addition to studying the inhibitors in breast cancer models, they will also explore how they work in cell systems that model brain tumors, rheumatoid arthritis and viral infections.

– by Leigh MacMillan

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